Orthopaedic Surgical Site Infections (SSIs), including Prosthetic Joint Infections (PJIs), are an extremely costly health care problem, illustrated by the $70,000-$114,000 average total cost per case to treat more than 20,000 hip and knee replacement infections in the US each year. When a prosthetic joint becomes infected following arthroplasty, organisms form a biofilm on the prosthesis and become inaccessible to systemically delivered antibiotics or immune cells. There is no available option for antimicrobial delivery over the entire surface of a prosthetic joint that is press-fit directly into a bony implantation site, as the vast majority of implants are. Such a technology would provide a real benefit to patients and could decrease the current costs of treating these infections by approximately $2,000,000,000 per year. A promising approach for preventing infections following joint replacement is to use reasorbable in situ forming gels for the sustained release of antimicrobial drugs. These new gels offer the following advantages for improved prevention of prosthetic joint infections: 1) efficient and sustained antibiotic release; 2) soft yet cohesive physical structure allowing for complete surface coverage and preventing the development of biofilm in isolated crevasses, and 3) rapid degradability allowing for normal bone healing, fixing the implant in place. The goal of the proposed work is to generate critical in vivo safety and efficacy data to support future investment in pre-clinical and clinical trials on these new, synthetic, and fully resorbable antimicrobial-releasing gels. To do this, in situ forming hydrogels will be evaluated with respect to their safety and two clinically relevant outcomes-the quality of bone healing through the gel site and the efficacy of antibiotic-loaded gels in preventing infection on press-fit metal implants. Bone healing through the gel site will be evaluated by histology and load frame testing in a rabbit cancellous bone press-fit implant model. The efficacy in preventing infection will be evaluated by press-fitting textured metal implants subjected to S. aureus into a void in cancellous bone pre-filled with antimicrobial- loaded gels. Successful completion of the proposed work will provide clinically relevant proof-of- principle data regarding the safety and efficacy of these hydrogels and in particular their use on the surface of orthopaedic implants. This data will immediately be used to lead to a pre-IND meeting with the FDA and will attract future investment for the commercialization of this new drug product.